EP1341530A1 - Utilisation d'un agoniste de dopamine ayant une demi-vie courte pour le traitement de maladies pouvant etre traitees par voie dopaminergique - Google Patents

Utilisation d'un agoniste de dopamine ayant une demi-vie courte pour le traitement de maladies pouvant etre traitees par voie dopaminergique

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Publication number
EP1341530A1
EP1341530A1 EP01969648A EP01969648A EP1341530A1 EP 1341530 A1 EP1341530 A1 EP 1341530A1 EP 01969648 A EP01969648 A EP 01969648A EP 01969648 A EP01969648 A EP 01969648A EP 1341530 A1 EP1341530 A1 EP 1341530A1
Authority
EP
European Patent Office
Prior art keywords
use according
tts
matrix
life
dopamine agonist
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP01969648A
Other languages
German (de)
English (en)
Inventor
Karsten Kuhn
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Axxonis Pharma AG
Original Assignee
Schering AG
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Schering AG filed Critical Schering AG
Publication of EP1341530A1 publication Critical patent/EP1341530A1/fr
Withdrawn legal-status Critical Current

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/70—Web, sheet or filament bases ; Films; Fibres of the matrix type containing drug
    • A61K9/7023—Transdermal patches and similar drug-containing composite devices, e.g. cataplasms
    • A61K9/703—Transdermal patches and similar drug-containing composite devices, e.g. cataplasms characterised by shape or structure; Details concerning release liner or backing; Refillable patches; User-activated patches
    • A61K9/7038—Transdermal patches of the drug-in-adhesive type, i.e. comprising drug in the skin-adhesive layer
    • A61K9/7046—Transdermal patches of the drug-in-adhesive type, i.e. comprising drug in the skin-adhesive layer the adhesive comprising macromolecular compounds
    • A61K9/7053—Transdermal patches of the drug-in-adhesive type, i.e. comprising drug in the skin-adhesive layer the adhesive comprising macromolecular compounds obtained by reactions only involving carbon to carbon unsaturated bonds, e.g. polyvinyl, polyisobutylene, polystyrene
    • A61K9/7061—Polyacrylates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/48—Ergoline derivatives, e.g. lysergic acid, ergotamine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A61P25/16—Anti-Parkinson drugs

Definitions

  • the invention relates to the use of an agent comprising a transdermal therapeutic system (TTS) with a dopamine agonistic active ingredient with a short half-life for the treatment of diseases which can be treated with dopaminergic, the TTS being applied in the evening before going to bed.
  • TTS transdermal therapeutic system
  • TTS includes in particular percutaneously acting, but also transmucosal systems.
  • a TTS is typically of a flat structure and is applied, for example, to the skin.
  • a TTS usually comprises a matrix containing an active substance (possibly in salt form) and / or an active substance reservoir and a diffusion barrier permeable to the active substance on the skin side of the active substance reservoir. Attachment to the skin can be carried out using an additional adhesive on the skin side (and for the active ingredient per eables). Likewise, the matrix and / or the diffusion barrier itself can be provided with adhesive properties. Finally, a non-adhesive TTS can be brought into contact with the skin by means of further aids, for example adhesive tapes or bandages.
  • a matrix is a substance in which the active ingredient is immobilized.
  • the active substance is not necessarily immobilized in an active substance reservoir, which is why the active substance reservoir must be encased.
  • the part of the jacket on the skin side is formed by the diffusion barrier. It goes without saying that the further part of the jacket should be as impermeable as possible, also with regard to diffusion paths, for the active substance.
  • immobilized means that no uncontrolled flow of active substance is possible.
  • diffusion of an active ingredient in a matrix and / or through a diffusion barrier is not only possible, but set up specifically.
  • the diffusion coefficients ultimately determine the flux of the active ingredient from the TTS into a patient's skin.
  • the dose delivered to the skin of a patient is therefore a linear approximation of the effective area of the patient
  • the effective area is the contact area of areas of the TTS that are open to diffusion for active substances.
  • a TTS of the structure mentioned above with lisuride as active ingredient and its use for the treatment of Parkinson's disease is known in principle from the literature reference WO 92/20339. This particularly describes the effect of propylene glycol lauric acid on the flux, which achieves a considerable increase in flux.
  • a TTS containing lisuride is also known from literature reference WO 91/00746.
  • Parkinson's disease and other health disorders are serious chronic and disabling illnesses, which in practice are caused by the oral administration of a combination of dopa-inert substances be treated.
  • This typically includes various formulations of levodopa (fast-flowing, normal or slow release), levodopa enhancers (optional COMT inhibitors, MAO-B inhibitors and definitely decarboxylase inhibitors as a base) and various dopamine agonists such as bromocriptine , Lisurid, Cabergolin, Ropinirol, Pramipexol, Pergolid, as well as Amantadine and occasionally anticholinergic agents.
  • levodopa which is a very fast-acting active ingredient, has pharmacokinetics that are difficult to control, and dopamine agonists also do not allow reliable predictions regarding the bioavailability and consequently the effective action.
  • a more continuous or discontinuous dopaminergic stimulation may be required.
  • Overdoses can also result from severe dyskinesia, dystonia or, especially after prolonged therapy with levodopa and / or agonists (in elderly patients), due to a narrow therapeutic window of time of all these dopaminergic active substances.
  • the latter serious problem is particularly associated with high plasma concentrations of the active ingredient at night, which are known to destroy normal sleep patterns and prevent normal REM sleep (with REM rebound at day time as the first sign of psychosis).
  • the patient's attitude towards side effects is usually in hospital in more or less specialized hospitals for several weeks.
  • the invention is based on the technical problem of specifying an agent and a treatment plan for the treatment of diseases which can be treated with dopaminergic, disruptive side effects being avoided, or at least reduced, and the active ingredient being flooded in a controlled manner and the duration of action being easily controllable on account of the short half-life.
  • the invention teaches the use of a dopamine agonist active substance with a short half-life in the form of an agent consisting of at least one spatially separated composition, one of which contains a transdermal agent containing the dopamine agonist active substance with a short half life is therapeutic system (TTS), for the treatment of dopaminerg treatable diseases, whereby the TTS is renewed at night or in the evening before going to bed.
  • TTS therapeutic system
  • the invention teaches the use of a dopamine agonist drug with a short half-life in the form of one consisting of at least two spatially separated compositions
  • TTS transdermal therapeutic system
  • the dopaminergic treatment covers 20 diseases from the group "Parkinsonism and in particular Parkinson's disease".
  • a transdermal therapeutic system also improves this Compliance, which is very important for the combination therapies of this disease and its mostly elderly patients.
  • better controllability and the night application of the patch offer a previously unreached width of the therapeutic window in the treatment of Parkinson's.
  • the dopamine agonist active ingredient can be in the form of the free base or in the form of the physiologically acceptable salt.
  • Suitable salts are, for example, sulfates, phosphates, maleates, citrates and succinates and, in particular, hydrogen maleate.
  • the dopamine agonistic active ingredient is preferably an ergoline derivative of the formula I or its physiologically compatible salt with an acid
  • R 1 is an H atom or a halogen atom, in particular a bromine atom
  • R 2 is Cl-4-alkyl, in particular methyl
  • Possible ergoline derivatives are in particular: lisuride, bromoisuride (3- (2-bromo-9, 10-didehydro-6-methyl-8 ⁇ -ergolinyl) -1, 1-diethylurea), terguride (3- (6-methyl-8 ⁇ -ergolinyl) -1, 1-diethylurea) and proterguride (3- (6-propyl-8 ⁇ -ergo-linyl) -1, 1-diethylurea).
  • the ergoline derivative lisuride (3- (9, 10-didehydro-6-methyl-8-ergolinyl) -1, 1-diethylurea) or its physiologically compatible salt with an acid is preferred.
  • the Production of lisuride and the other ergolines suitable according to the invention is described for example in US 3,953,454, EP 056 358 and US 4,379,790.
  • the clinical advantages of such a lag time are the first-time consideration of potential desensitization (loss of activity) through continuous stimulation of the receptors. The receptors regulate down again during this time and are then sensitive enough to be stimulated again with the next Lisurid night patch. During the night (here after midnight) this is temporarily below the therapeutic level
  • the treatment is supplemented by the administration of oral preparations of L-DOPA, optionally in combination with decarboxylase inhibitors such as benserazide or carbidopa.
  • decarboxylase inhibitors such as benserazide or carbidopa.
  • the TTS has a drug layer which has at least one matrix containing an active ingredient and / or an active ingredient reservoir and an active ingredient permeable to the skin side of the active ingredient reservoir
  • Diffusion barrier and as an active ingredient with a short half-life contains an ergoline derivative according to formula I or its physiologically compatible salt with an acid, the ergoline derivative having a half-life of 0.5 to 4 hours, in particular 1 to 2 hours, and falling short the therapeutic threshold is reached for a period of 1 to 4 hours, in particular 1 to 3 hours.
  • the matrix and / or the diffusion barrier can be selected with the proviso that the transdermal Flow F through human skin, measured according to Example 1, is in the range from 0.1 to 5.0 ⁇ g / cm / h. F and effective area are preferably selected so that therapeutic plasma levels of 0.1 to 2 ng / ml are established.
  • the ergoline derivative is preferably lisuride base.
  • a cover layer can be arranged on the side of the matrix and / or the active substance reservoir facing away from the skin.
  • the preparation in tablet form prepared for oral administration preferably contains 25 to 1000 ⁇ g L-DOPA (per tablet).
  • the amount of the individual active substances per day, based on the neutral compound, in an oral dose is from L-DOPA 50 to 700 mg / day, from benserazide 12.5 to 200 mg / day and from Carbidopa 25 to 175 mg / day.
  • the TTS can be designed in detail as follows.
  • a cover layer can be arranged on the side of the matrix and / or the active substance reservoir facing away from the skin. This can be formed, for example, with films made of polyethylene or polyester. The thickness is typically 10 to 100 ⁇ m.
  • Metallization is the application of a very thin layer (typically less than 1 ⁇ m, usually in the 10-100 nm range) of a metal, for example aluminum, to the top layer.
  • Pigments can all pigments commonly used in the coating agents, too Effect pigments, provided that they are physiologically harmless.
  • a removable liner can be provided on the application side, for example a siliconized or fluoropolymer-coated polymeric protective film.
  • the matrix and / or diffusion barrier can be a substance selected from the group consisting of "polyacrylate, polyurethane, cellulose ether, silicone, polyvinyl compounds, polyisobutylene compounds,
  • a main matrix component forms at least 50% by weight, for example at least 80-90% by weight, of the matrix (the term matrix refers to the finished one Layer, ie main matrix component (s) with auxiliary substance (s) and active substance (s) .
  • the desired flux is set on the one hand by selecting the substance depending on the
  • the thickness range of a matrix is typically in the range from 10 ⁇ m to 500 ⁇ m.
  • a particularly preferred polyacrylate adhesive as the main matrix component is commercially available under
  • the diffusion barrier can alternatively have a polymer selected from the group consisting of "cellulose esters, cellulose ethers, silicone, polyolefin and mixtures and copolymers of these substances" as the main barrier component.
  • cellulose esters, cellulose ethers, silicone, polyolefin and mixtures and copolymers of these substances as the main barrier component.
  • the diffusion barrier can be designed as a film with a thickness of 10 ⁇ m to 300 ⁇ m, the thickness of the layer (in conjunction with the diffusion coefficient of the active ingredient in the polymer) being adjusted in accordance with the desired flux.
  • the matrix and / or the drug reservoir and / or the diffusion barrier can contain auxiliaries customary for TTS.
  • a penetration-enhancing agent which is preferably selected from the group consisting of "C1-C8 aliphatic, cycloaliphatic and aromatic alcohols, saturated and unsaturated C8-18 fatty alcohols, saturated and unsaturated C8-18 fatty acids, hydrocarbons and hydrocarbon mixtures, is preferably used as auxiliary. Fatty acid esters from C3-19 fatty acids and Cl-6 alkyl monools, Dicarboxylic acid diesters from C4-8 dicarboxylic acids and Cl- 6 alkyl monools, and mixtures of these substances.
  • Penetration enhancing agents improve the flux of the active ingredient through the skin to which the TTS is applied. Examples from the above
  • Substances are: 1, 2-propanediol, menthol, dexpanthenol, benzyl alcohol, lauryl alcohol, isocetyl alcohol, cetyl alcohol, mineral oil, lauric acid, isopalmitic acid, isostearic acid, oleic acid; Methyl ester, ethyl ester, 2-hydroxyethyl ester, glycerol ester, propyl ester, isopropyl ester, butyl ester, sec-butyl ester or isobutyl ester of lauric acid, myristic acid, stearic acid or palmitic acid.
  • Lauryl alcohol most preferred from lauryl alcohol.
  • Crystallization inhibitors are suitable as further auxiliaries. Crystallization inhibitors are highly disperse silicon dioxide or macromolecular substances such as
  • Plyvinylpyrrolidone polyvinyl alcohols, dextrins, sterols, bile acids and, in particular polyvinylpyrrolidone-vinyl acetate copolymers suitable as Kollidon ® VA 64th
  • the lauryl alcohol preferably forms 10 to 30% by weight, most preferably 15 to 20% by weight, of the matrix.
  • the auxiliary substances can in principle form 0 to 50% by weight of the matrix.
  • the active ingredient can form 0.5 to 20% by weight, preferably 1 to 10% by weight, of the matrix. The sum of the proportions of the main matrix component, auxiliary substances and active substances always forms 100% by weight.
  • the dose of the active ingredient in a human body carrying the TTS depends not only on the above diffusion-related properties of the TTS but also on its effective area with the skin. Effective area means the area with which the matrix or the diffusion barrier comes to rest against the skin.
  • the variation preferably takes place in accordance with the desired dose in a range from 1 to 100 cm 2 .
  • patient-specific dose variations can be set up by a doctor, namely by choosing a suitable size. The treatment can thus be easily adjusted to different body weights, age groups, etc.
  • TTS which has a (rather large) standard area, with division markings for partial doses, so that a user can only cut off and use a section corresponding to a certain dose.
  • Corresponding imprints can easily be attached to the top layer.
  • a FRANZ flow diffusion cell is used for the flux measurement.
  • the measuring area is 2 cm 2 .
  • 4 cm 2 ventral and dorsal skin of a male hairless mouse (MFl hr / hr Ola / Hsd, available from Harlan Olac, UK) are used, carefully removing subcutaneous adipose tissue.
  • a 2 cm 2 TTS is applied to the skin used.
  • the acceptor medium is arranged opposite. It is dilute HHBSS (Hepes Hanks Balanced Salt Solution) containing 5.96 g / 1 Hepes, 0.35 g / 1 NaHC0 3 and 0.1 ml / 1 lOx HBSS (available from Gibco, Eggenstein, DE).
  • 1000 IU / ml penicillin (benzylpenicillin potassium salt, available from Fluka, Neu-Ulm, DE).
  • the measurement is carried out in detail as follows.
  • the TTS to be measured is first applied to the skin.
  • the skin is mounted in the diffusion cell.
  • 1 ml of acceptor medium are pumped through the diffusion cell per hour using a peristaltic pump.
  • the temperature of the acceptor medium is controlled by means of a circulating water bath and keeps the surface of the skin at a temperature of 31 ° C with 1 ° C accuracy.
  • the drug concentration in the acceptor medium is determined according to the following details using a radioimmunoassay.
  • Calibration curves These are constructed using two different methanol solutions of non-radioactive lisuride hydrogen maleate salt, each containing 1 mg / ml. These solutions are different with BSA buffer (0.041 M Na2HP ⁇ 2 * 2H2 ⁇ ,
  • Lisurid free base concentrations in the range of 1000 - 3.9 pg / 0.1 ml.
  • a drug-free sample Opg
  • the calibration samples are analyzed in triplicate.
  • the Lisurid concentrations are calculated using the pharmacokinetic RIO PC software, 2.5 (other conventional software can also be used).
  • Range of the calibration curve 100 ⁇ l of diluted sample are directly subjected to radioimmunological analysis.
  • the antiserum (rabbit) can be obtained by immunization with the immunogen Lisurid-1
  • succinyl-BSA succinyl-BSA.
  • the dilution of the antiserum in the assay is 1: 12500.
  • Tracer 3 H-Lisuride hydrogen maleate with a specific activity of 4.3 GBq / mg is used. Incubation: 0.7 ml BSA buffer with active ingredient, 0.1 ml tracer solution (approx. 5000 cpm / 0.1 ml BSA buffer) and 0.1 ml diluted antiserum (1: 12500) and it is incubated at 4 ° C. for 18 h.
  • Antibody-bound lisuride is freed by adding 0.2 ml charcoal suspension (1.25% (w / v) and 0.125% (w / v) dextran in BSA buffer) and incubation for 30 min. separated at 0 ° C.
  • Charcoal is centrifuged at 3000 g for 15 min. sedimented.
  • the supernatant (containing antibody-bound active ingredient) is decanted and sent for radiometric analysis.
  • Radiometric analysis 4 ml of the Atomlight (NEN) scintillation cocktail are added to the supernatant. The counting is done with a WALLAC 1409 or 1410 ß scintillation counter without quench control.
  • the percutaneous skin flux is calculated as follows:
  • F is the percutaneous flux [ng / cm 2 / h]
  • C the active substance concentration in the acceptor medium [ng / ml]
  • RdenAcceptor medium flow [lml / h]
  • A the measuring area [2cm 2 ]
  • T the sampling time interval [h].
  • Measurements of the flux according to Example 1 give F a day 1 value of 0.43, a day 2 value of 0.44 and a maximum F of 0.85 (each in ⁇ g / cm 2 / h).
  • Measurements of the flux according to Example 1 give F a day 1 value of 0.90, a day 2 value of 1.76 and a maximum F of 2.53 (each in ⁇ g / cm 2 / h).

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  • Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Engineering & Computer Science (AREA)
  • Epidemiology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Dermatology (AREA)
  • Biomedical Technology (AREA)
  • Neurology (AREA)
  • Neurosurgery (AREA)
  • Psychology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Medicinal Preparation (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne l'utilisation d'un agent actif agoniste de dopamine ayant une demi-vie courte, sous forme d'un système thérapeutique transdermique pour le traitement de maladies pouvant être traitées par voie dopaminergique.
EP01969648A 2000-12-16 2001-08-24 Utilisation d'un agoniste de dopamine ayant une demi-vie courte pour le traitement de maladies pouvant etre traitees par voie dopaminergique Withdrawn EP1341530A1 (fr)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
DE10064453A DE10064453A1 (de) 2000-12-16 2000-12-16 Verwendung eines dopaminergen Wirkstoffes zur Behandlung von dopaminerg behandelbaren Erkrankungen
DE10064453 2000-12-16
PCT/EP2001/009822 WO2002047666A1 (fr) 2000-12-16 2001-08-24 Utilisation d'un agoniste de dopamine ayant une demi-vie courte pour le traitement de maladies pouvant etre traitees par voie dopaminergique

Publications (1)

Publication Number Publication Date
EP1341530A1 true EP1341530A1 (fr) 2003-09-10

Family

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Family Applications (1)

Application Number Title Priority Date Filing Date
EP01969648A Withdrawn EP1341530A1 (fr) 2000-12-16 2001-08-24 Utilisation d'un agoniste de dopamine ayant une demi-vie courte pour le traitement de maladies pouvant etre traitees par voie dopaminergique

Country Status (5)

Country Link
US (1) US20040219191A1 (fr)
EP (1) EP1341530A1 (fr)
AU (1) AU2001289837A1 (fr)
DE (1) DE10064453A1 (fr)
WO (1) WO2002047666A1 (fr)

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